Endocannabinoid (EC) signaling has recently been recognized to play an important role in the metabolic syndrome. In obesity and insulin resistance, EC levels are increased in the hypothalamus and in peripheral organs like liver and adipose tissue. Results from clinical studies in humans with type 2 diabetes mellitus (type2 DM) indicate that pharmacologic cannabinoid receptor (CB) 1 blockade improves glucose homeostasis. The mechanisms by which ECs participate in the regulation of glucose homeostasis are poorly defined, but are thought to either involve central, hypothalamic effects and/or direct effects in target organs like liver and adipose tissue. In neurons ECs have the ability to act as retrograde messengers to suppress transmitter release via activation of presynaptic CB1 receptors. In the periphery CB1 activation has been shown to induce lipogenesis in liver and adipose tissue. We have recently shown that EC tone in adipose tissue is suppressed by hypothalamic leptin signaling, suggesting that the increased EC tone in obesity and type 2 DM is a consequence of central leptin resistance. The medio- basal hypothalamus (MBH) plays a pivotal role in the brain regulation of hepatic glucose production. Circulating hormones like insulin and leptin signal through their respective receptors in the MBH. This in turn leads to the activation of descending pathways that result in the suppression of hepatic glucose production and the modulation of lipid metabolism. We have found that in a model of short term (3 days) overfeeding induced insulin resistance, insulin infused into the MBH looses its ability to suppress hepatic glucose production, while insulin signaling is intact in liver and the hypothalamus of this model. Thus, we speculate that increased ECs in the hypothalamus exert an inhibitory effect on insulin induced neuronal transmission. The two aims of this proposal are to 1. Delineate the role of central EC signaling in the regulation of hepatic glucose production and to 2. Investigate if hypothalamic EC levels can be modulated by ECs that originate from adipose tissue. These studies should advance our understanding of why excessive nutrient intake leads to increased EC tone and impaired brain control of metabolism in adipose tissue and liver. It is well established that a tight relationship exists between obesity and type 2 diabetes. Weight gain worsens glucose control and conversely, weight loss improves glycemic control and thereby decreases the risk of diabetic complications. Here we wish to understand how hormones that play important roles in energy homeostasis, leptin and EC control glucose homeostasis advancing our understanding of pathophysiology and treatment of diabetes.